European urology oncology · 2025
Multiregional Immune Profiling Reveals Prognostic Patterns in Bladder Cancer.
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Jurczok Nadia, Dernbach Gabriel, Ebner Benedikt, Plage Henning, Dragomir Mihnea P, Keyl Philipp, Ribbat-Idel Julika, Ramberger Evelyn, Roßner Florian, Quaas Alexander, Sauter Guido, Schlomm Thorsten, Klauschen Frederick, Stief Christian, Horst David, Schulz Gerald Bastian, Eich Marie-Lisa, Schallenberg Simon
Аннотация
BACKGROUND AND OBJECTIVE: Muscle-invasive bladder cancer (MIBC) is a biologically heterogeneous disease with variable prognosis after radical cystectomy. While conventional clinicopathological parameters offer limited prognostic value, growing evidence highlights the role of the tumor immune microenvironment (TIME)-including immune cell composition and spatial architecture-as robust biomarkers for disease progression and outcomes.
METHODS: The study included 251 consecutive patients with MIBC who underwent cystectomy (2004-2014, LMU Munich). Three 1-mm-diameter cores were sampled from the tumor invasive front and center in the cystectomy specimen. Six immune checkpoint proteins (ICPs; IDO, PD-L1, PD-1, LAG-3, TIM-3, and VISTA) were quantified digitally following immunohistochemical (IHC) staining. ICP-positive immune and tumor cells were stratified and densities were hierarchically clustered. Multivariable Cox models were then used to assess the association with overall (OS) and disease-free survival. The minimum tumor sample count needed to detect the maximum ICP expression per patient was estimated via a 1000-fold bootstrap resampling simulation.
KEY FINDINGS AND LIMITATIONS: IDO+ and VISTA+ immune cells dominated the TIME, while PD-L1+ tumor cells exhibited a dichotomous expression pattern. Analysis of three spatially distinct cores was sufficient to recover maximal expression of low-abundance TIM-3+ and VISTA+ immune cells, while four cores were required for all other markers. ICP-based clustering revealed three TIME subtypes (CID1-3), of which CID3 was associated with markedly worse prognosis (median OS 18.5 vs 100.5 mo; p = 0.0007). This classification outperformed Union for International Cancer Control staging and improved patient stratification in late-stage MIBC.
CONCLUSIONS AND CLINICAL IMPLICATIONS: A six-marker, multiregional ICP panel delivers a robust, stage-independent, actionable risk stratification in MIBC. At least four biopsies are advised for routine immune profiling; further longitudinal external validation is warranted.
METHODS: The study included 251 consecutive patients with MIBC who underwent cystectomy (2004-2014, LMU Munich). Three 1-mm-diameter cores were sampled from the tumor invasive front and center in the cystectomy specimen. Six immune checkpoint proteins (ICPs; IDO, PD-L1, PD-1, LAG-3, TIM-3, and VISTA) were quantified digitally following immunohistochemical (IHC) staining. ICP-positive immune and tumor cells were stratified and densities were hierarchically clustered. Multivariable Cox models were then used to assess the association with overall (OS) and disease-free survival. The minimum tumor sample count needed to detect the maximum ICP expression per patient was estimated via a 1000-fold bootstrap resampling simulation.
KEY FINDINGS AND LIMITATIONS: IDO+ and VISTA+ immune cells dominated the TIME, while PD-L1+ tumor cells exhibited a dichotomous expression pattern. Analysis of three spatially distinct cores was sufficient to recover maximal expression of low-abundance TIM-3+ and VISTA+ immune cells, while four cores were required for all other markers. ICP-based clustering revealed three TIME subtypes (CID1-3), of which CID3 was associated with markedly worse prognosis (median OS 18.5 vs 100.5 mo; p = 0.0007). This classification outperformed Union for International Cancer Control staging and improved patient stratification in late-stage MIBC.
CONCLUSIONS AND CLINICAL IMPLICATIONS: A six-marker, multiregional ICP panel delivers a robust, stage-independent, actionable risk stratification in MIBC. At least four biopsies are advised for routine immune profiling; further longitudinal external validation is warranted.